Keywords
Alzheimer’s disease
Neuroprotection
Natural products
Submitted : 2026-02-17
Accepted : 2026-03-04
Published : 2026-03-19
Abstract
Neurodegenerative diseases (NDs) encompass a spectrum of chronic, progressive disorders defined by the insidious loss of neuronal structure and function, the multifactorial etiologies of which remain incompletely understood. To date, clinical interventions for NDs have primarily targeted four domains: neuroprotection, the clearance of aberrant protein aggregates, restoration of neurotransmitter homeostasis, and suppression of neuroinflammation. However, most conventional pharmacotherapies provide only palliative symptomatic relief rather than addressing the fundamental etiological drivers of NDs. Furthermore, their clinical utility is often hampered by off-target effects and a mono-targeted approach, which fails to counteract the multifaceted nature of disease progression. Conversely, natural products derived from traditional Chinese medicine (TCM) offer unique advantages, characterized by high biocompatibility, minimal toxicity, and the capacity for pleiotropic regulation through multi-target synergistic mechanisms, ranging from the preservation of cellular homeostasis to the modulation of the neuro-microenvironment and the promotion of neuroplasticity and regeneration. Focusing on gallic acid (GA) as a prototypical bioactive polyphenolic compound, this review provides a comprehensive synthesis of recent advances and the molecular underpinnings of its neuroprotective and neurorestorative effects, offering critical insights and a theoretical framework for the development of TCM-derived candidates as novel neurotherapeutics.
References
Baufeld C, O’Loughlin E, Calcagno N, et al., 2018, Differential Contribution of Microglia and Monocytes in Neurodegenerative Diseases. Journal of Neural Transmission (Vienna), 125(5): 809–826.
Armstrong R, 2020, What Causes Neurodegenerative Disease? Folia Neuropathologica, 58(2): 93–112.
Maji M, Khajanchi S, 2025, Mathematical Models on Alzheimer’s Disease and its Treatment: A Review. Physics of Life Reviews, 2025(52): 207–244.
Dorsey ER, Sherer T, Okun MS, et al., 2018, The Emerging Evidence of the Parkinson Pandemic. Journal of Parkinson’s Disease 2018(8): S3–S8.
Redman RR, Mackenzie H, Dissanayake KN, et al., 2022, Donepezil Inhibits Neuromuscular Junctional Acetylcholinesterase and Enhances Synaptic Transmission and Function in Isolated Skeletal Muscle. British Journal of Pharmacology, 179(24): 5273–5289.
Brewster JT 2nd, Dell’Acqua S, Thach DQ, 2019, Classics in Chemical Neuroscience: Donepezil. ACS Chemical Neuroscience, 10(1): 155–167.
Shafiei-Irannejad V, Abbaszadeh S, Janssen PML, et al., 2021, Memantine and its Benefits for Cancer, Cardiovascular and Neurological Disorders. European Journal of Pharmacology, 5(910): 174455.
Puranik N, Song M, 2024, Glutamate: Molecular Mechanisms and Signaling Pathway in Alzheimer’s Disease, a Potential Therapeutic Target. Molecules, 29(23): 5744.
Yu SP, Jiang MQ, Shim SS, et al., 2023, Extrasynaptic NMDA Receptors in Acute and Chronic Excitotoxicity: Implications for Preventive Treatments of Ischemic Stroke and Late-onset Alzheimer’s Disease. Molecular Neurodegeneration, 18(1): 43.
Pușcașu C, Chiriță C, Negreș S, et al., Exploring the Therapeutic Potential of N-Methyl-D-Aspartate Receptor Antagonists in Neuropathic Pain Management. International Journal of Molecular Sciences, 25(20): 11111.
Bai J, Zhang Y, Tang C, et al., 2021, Gallic Acid: Pharmacological Activities and Molecular Mechanisms Involved in Inflammation-related Diseases. Biomedicine & Pharmacotherapy, 2021(133): 110985.
Sanz Del Olmo N, Peña González CE, Rojas JD, et al., 2020, Antioxidant and Antibacterial Properties of Carbosilane Dendrimers Functionalized with Polyphenolic Moieties. Pharmaceutics, 12(8): 698.
Gutiérrez-Del-Río I, López-Ibáñez S, Magadán-Corpas P, et al., 2021, Terpenoids and Polyphenols as Natural Antioxidant Agents in Food Preservation. Antioxidants (Basel), 10(8): 1264.
Sorrentino E, Succi M, Tipaldi L, et al., 2018, Antimicrobial Activity of Gallic Acid Against Food-related Pseudomonas Strains and its Use as Biocontrol Tool to Improve the Shelf Life of Fresh Black Truffles. International Journal of Food Microbiology, 2018(266): 183–189.
Huang B, Zhang Z, Ding N, et al., 2021, Investigation of the Pectin Grafting with Gallic Acid and Propyl Gallate and their Antioxidant Activities, Antibacterial Activities and Fresh Keeping Performance. International Journal of Biological Macromolecules, 2021(190): 343–350.
Yan M, Huang S, Li X, et al., 2025, Gallic Acid Nanocrystal Hydrogel: A Novel Strategy for Promoting Wound Healing and Inhibiting Scar Formation. International Journal of Nanomedicine, 2025(20): 4607–4626.
Garg S, Jana A, Gupta S, et al., 2025, Discovery of Gallic Acid-based Mitochondriotropic Antioxidant Attenuates LPS-induced Neuroinflammation. Free Radical Biology and Medicine, 2025(226): 302–329.
Huang J, Wu F, Cao W, et al., 2025, Ultrasmall Iron-gallic Acid Coordination Polymer Nanoparticles for Scavenging ROS and Suppressing Inflammation in Tauopathy-induced Alzheimer’s Disease. Biomaterials, 2025(317): 123042.
Dastan M, Rajaei Z, Sharifi M, et al., 2024, Gallic Acid Ameliorates LPS-induced Memory Decline by Modulating NF-κB, TNF-α, and Caspase 3 Gene Expression and Attenuating Oxidative Stress and Neuronal Loss in the Rat Hippocampus. Metabolic Brain Disease, 40(1): 12.
Ojo OA, Rotimi DE, Ojo AB, et al., 2023, Gallic Acid Abates Cadmium Chloride Toxicity via Alteration of Neurotransmitters and Modulation of Inflammatory Markers in Wistar Rats. Scientific Reports, 13(1): 1577.
Agostini JF, Santo GD, Baldin SL, et al., 2021, Wanderley AG. Gallic Acid Reverses Neurochemical Changes Induced by Prolonged Ethanol Exposure in the Zebrafish Brain. Neuroscience, 2021(455): 251–262.
Meftahi GH, Aboutaleb N, 2023, Gallic Acid Ameliorates Behavioral Dysfunction, Oxidative Damage, and Neuronal Loss in the Prefrontal Cortex and Hippocampus in Stressed Rats. Journal of Chemical Neuroanatomy, 2023(134): 102364.
Recart VM, Spohr L, de Aguiar MSS, et al., 2024, Gallic Acid Attenuates Lipopolysaccharide-induced Memory Deficits, Neurochemical Changes, and Peripheral Alterations in Purinergic Signaling. Metabolic Brain Disease, 40(1): 43.
Abbasalipour H, Hajizadeh Moghaddam A, Ranjbar M, 2022, Sumac and Gallic Acid-loaded Nanophytosomes Ameliorate Hippocampal Oxidative Stress via Regulation of Nrf2/Keap1 Pathway in Autistic Rats. Journal of Biochemical and Molecular Toxicology, 36(6): e23035.
Dong XJ, 2022, Study on the Effect and Mechanism of Gallic Acid in Improving Hypoxic-ischemic Brain Injury in Neonatal Rats by Inhibiting Neuroinflammation, thesis, Chongqing Medical University, Chongqing.
Jiang DQ, Yang XF, Chen XS, et al., 2020, Protective Effect of Gallic Acid on Dopaminergic Neurons in MPTP-induced Parkinson’s Disease. Chinese Pharmaceutical Journal, 55(11): 908–912.
Karaaslanlı A, Tuncer MC, Aşır F, et al., 2025, Gallic Acid Showed Neuroprotection against Endoplasmic Reticulum Stress in Rats. Acta Cirurgica Brasileira, 2025(40): e400925.
Chen KW, 2025, Study on the Improvement Effect and Mechanism of Allylcysteine and Gallic Acid Conjugates on Alzheimer’s Disease, thesis, Guangzhou University.
Ilyas Isa, Fu J, Amina S, 2024, Research Progress on the Mechanism of Mitochondrial Dysfunction in Alzheimer’s Disease Patients. Shandong Medicine, 64(9): 91–94.
Lin LT, 2025, CaGA Nanozymes for the Treatment of Ulcerative Colitis by Inhibiting Oxidative Stress and Protecting Mitochondrial Function, thesis, Anhui Medical University.
Chen S, Lu B, Bi K, et al., 2023, Glycyrrhizic Acid Inhibits the Growth of Glioma Cells by Activating TRPV4-induced Mitophagy. Journal of Modern Oncology, 31(15): 2776–2781.
Diao JW, 2024, Inhibitory Effect of Gallic Acid on LPS-induced Inflammatory Response in Human THP-1 Macrophages, thesis, Yanbian University.
Qin SC, Wang AM, Wan XB, 2020, Study on the Antioxidant Mechanism of Gallic Acid in 6-hydroxydopamine-induced Parkinson’s Model Rats. Pharmacology and Clinics of Chinese Materia Medica, 36(6): 86–90.
Wang Q, Xiong XF, Feng J, et al., 2025, Protective Effect of Epigallocatechin Gallate against Lead-induced Neuronal Damage in Mice by Regulating Mitochondrial Homeostasis. Practical Preventive Medicine, 32(7): 807–813.
Ma YD, Liu H, Chen Q, et al., 2025, Gallic Acid and Loganic Acid Attenuate Amyloid-β Oligomer-induced Microglia Damage via NF-κB Signaling Pathway. Neuropharmacology, 1(263): 110215.
Sun J, Ren DD, Wan JY, et al., 2017, Desensitizing Mitochondrial Permeability Transition by ERK-Cyclophilin D Axis Contributes to the Neuroprotective Effect of Gallic Acid against Cerebral Ischemia/Reperfusion Injury. Frontiers in Pharmacology, 2017(8): 184.
Li YY, Qin ZH, Sheng R, 2024, The Multiple Roles of Autophagy in Neural Function and Diseases. Neuroscience Bulletin, 40(3): 363–382.
Lin Y, Huang KW, Hong HH, et al., 2025, EGCG Blocks the HDAC6-PI3K/AKT/mTOR Axis to Activate Autophagy and Promote Microglial Clearance of Aβ. Journal of Sun Yat-sen University (Medical Sciences), 46(3): 486–497.
Sun CY, Jia N, Han K, 2020, Effect of Epigallocatechin Gallate on Cognitive Function and Hippocampal Autophagy in APP/PS1 Transgenic Mice. Chinese Pharmacological Bulletin, 36(4): 539–543.
Hua W, Xu H, Chen R, et al., 2025, Gallic Acid Alleviates Cerebral Ischemia-reperfusion Injury in Mice by Mediating Microglial Polarization Through the NLRP3/mTOR Axis. Journal of Neuroimmune Pharmacology, 20(1): 101.
Zhou X, Lu RR, Ren FL, et al., 2025, Effect of Epigallocatechin Gallate on MPTP-induced Parkinson’s Disease Model Mice through the Autophagy-Lysosome Pathway. The Journal of Practical Medicine, 41(8): 1097–1104.
Zhou X, Lu RR, Ren FL, et al., 2025, Effect of Epigallocatechin Gallate on MPTP-induced Parkinson’s Disease Model Mice Through the Autophagy-lysosome Pathway. The Journal of Practical Medicine, 41(8): 1097–1104.
Xia XY, Wang DS, Lin BY, et al., 2025, Mechanism Study of Gallic Acid Targeting β-arrestin2 to Inhibit Astrocyte Inflammation. Journal of Nanjing University of Chinese Medicine, 41(3): 341–351.
Qu Y, Wang L, Mao Y, 2022, Gallic Acid Attenuates Cerebral Ischemia/re-perfusion-induced Blood-Brain Barrier Injury by Modifying Polarization of Microglia. Journal of Immunotoxicology, 19(1): 17–26.
Adedara IA, Owumi SE, Oyelere AK, et al., 2021, Neuroprotective Role of Gallic Acid in Aflatoxin B1-induced Behavioral Abnormalities in Rats. J Journal of Biochemical and Molecular Toxicology, 35(3): e22684.
Kim MJ, Seong AR, Yoo JY, et al., 2011, Gallic Acid, a Histone Acetyltransferase Inhibitor, Suppresses β-Amyloid Neurotoxicity by Inhibiting Microglial-mediated Neuroinflammation. Molecular Nutrition & Food Research, 55(12): 1798–1808.
Jiang J, Hai J, Liu W, et al., 2021, Gallic Acid Induces Neural Stem Cell Differentiation into Neurons and Proliferation through the MAPK/ERK Pathway. Journal of Agricultural and Food Chemistry, 69(42): 12456–12464.
Ding Y, He J, Kong F, et al., 2024, Gallic Acid Alleviates Cognitive Impairment by Promoting Neurogenesis via the GSK3β-Nrf2 Signaling Pathway in an APP/PS1 Mouse Model. Journal of Alzheimer’s Disease Reports, 8(1): 461–477.
Maya S, Prakash T, Madhu K, 2018, Assessment of Neuroprotective Effects of Gallic acid against Glutamate-induced Neurotoxicity in Primary Rat Cortex Neuronal Culture. Neurochemistry International, 2018(121): 50–58.
Chandrasekhar Y, Phani Kumar G, Ramya EM, et al., 2018, Gallic Acid Protects 6-OHDA Induced Neurotoxicity by Attenuating Oxidative Stress in Human Dopaminergic Cell Line. Neurochemical Research, 43(6): 1150–1160.
Zhu JX, Shan JL, Hu WQ, et al., 2019, Gallic Acid Activates Hippocampal BDNF-Akt-mTOR Signaling in Chronic Mild Stress. Metabolic Brain Disease, 34(1): 93–101.
Zhang SQ, 2025, Preparation of Gallic Acid@ZIF-8 Multifunctional Films and their Food Preservation Performance, thesis, Northwest A&F University.
Chen Y, 2024, Application of Chitosan-gallic Acid Preservative Solution in the Preservation of Larimichthys crocea, thesis, Zhejiang Ocean University.
Yin HF, 2023, Preparation and Performance Study of Bio-based Electrospun Antioxidant and Moisturizing Masks, thesis, Donghua University.
Zhang ZW, Li ZG, Li CX, 2024, Experimental Study of Gallic Acid Combined with Cisplatin Inhibiting Esophageal Cancer by Downregulating Cyclooxygenase-2. Chinese Journal of Integrated Traditional and Western Medicine in Surgery, 30(4): 562–567.
Lin Y, Luo T, Weng A, et al., 2020, Gallic Acid Alleviates Gouty Arthritis by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis Through Enhancing Nrf2 Signaling. Frontiers in Immunology, 2020(11): 580593.
Tekin GG, Deveci B, 2023, Effects of Gallic Acid on Gingival Wounds. European Review for Medical and Pharmacological Sciences, 27(7): 2739–2744.
Hong Y, Wang J, Sun W, et al., 2023, Gallic Acid Improves the Metformin Effects on Diabetic Kidney Disease in Mice. Renal Failure, 45(1): 2183726.
Wang Y, Wang F, Sun J, et al., 2025, Gallic Acid Ameliorates Skeletal Muscle Metabolic Inflexibility by Regulating Lactate Metabolism and Promoting Mitochondrial Function. Molecular Nutrition & Food Research, 69(16): e70106.